B Cells and Antibody Play Critical Roles in the Immediate De(5)

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infection, 10-foldhigherlevelsofWNVRNAweremeasuredviralRNAinmultipleregionsoftheCNS(Fig.3Banddatanotinthelymphnodesfrom MTmice(Fig.3C).

shown).Immunohistochemistrycorroboratedtheseresults(iii)Spleen.Inwild-typemice,thelevelsofinfectiousWNV(Fig.1).Prominentstainingforviralantigenwasobservedininthespleenpeakedatday4afterinfection,decreasedbydaythebrainstem,cerebralcortex,hippocampus,andcerebellum6,andwereabsentatday8.Althoughcomparablelevelswereof MTmice.Basedonhistologicalappearance,high-gradeobservedin MTmiceatdays4and6,therewasnoclearanceinfectionwasfoundtooccurprimarilyinneuronsand,inmanyphase,aslevelsofvirus(104PFU/g)persistedinthespleen elds,coincidedwithevidenceofneuronalinjuryorcelldeath.afterday6(Fig.3A).AsimilartrendwasobservedwhenviralThedifferenceinCNSviralloadsbetweenwild-typeand MTRNAlevelsweremeasured(datanotshown).

micewasnotexplainedbytheultimatebiasofthesurvival(iv)CNS.Similarlevelsofinfectiousvirusweredetectedincurves,becausenoindividualwild-typemousehadviraltitersthebrainandspinalcordofwild-typeand MTmiceat4daysinthebrainthatapproachedthoseinthe MTmice(e.g.,theafterinfection.Sinceinfectiousvirusappearedconcurrentlyatmaximumtiterinthebrainofawild-typemousewas5.5 105morethanonesiteintheCNS,WNVappearstospreadbyaPFU/ml)atanydayafterinfection.

hematogenousroute.Byday6,markedlyincreasedviralloads(v)Liver.TheabsenceofBcellsandantibodyaffectedtheweredetectedinthebrainandinferiorandsuperiorspinaltropismofWNVinfection.Inwild-typemice,noinfectiouscordof MTmice;byday8,B-cell-andantibody-de cientvirusandverylowlevelsofRNA( 2 102copiesofWNVmicehad100-to500-foldhigherlevelsofinfectiousvirusandRNAper gof18SrRNA)weremeasuredfrom

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